Hyper-expression of phosphodiesterase-10A in striato-nigral and striato-pallidal pathways of Torsin-A knock-in mice

Introduction: In most forms of dystonia there is uncertainty about brain regions primary involved, which are therefore thought to have functional rather than structural abnormalities. We report that changes of phosphodiesterase-10A (PDE10A) immunoreactivity map the involvement of the basal ganglia in TorsinA DYT1 knock-in mice, a transgenic model of the most common primary dystonia. PDE10A, a key enzyme in the catabolism of cAMP and cGMP, has unique distribution in the basal ganglia, within medium spiny neurons in the striatum, and in their axons/terminals in the substantia nigra pars reticulata and external globus pallidus. Material and methods: PDE10A was studied in control mice and in mice carrying either human wild-type torsinA or mutant torsinA. Rabbit anti-PDE10A was used for immunohistochemical identification of PDE10A neurons and nerve fibers. Quantitative analysis of PDE10A expressions in the different brain areas was assessed by Western blotting. Results: In control mice prominent PDE10A-like immunoreactivity was observed in neuronal bodies and in the neuropil throughout the caudate-putamen; moreover intense PDE10A-likeimmunoreactivity was observed in neuropil and nerve fibers of the globus pallidus, and substantia nigra pars reticulata. Biochemical and morphological studies demonstrate that PDE10A expression was clearly increased in the globus pallidus of mice carrying DYT1TorsinA mutation, while in substantia nigra the PDE10A immunoreactivity was overexpressed both in mice carrying wild-type human TorsinA and in mice carrying DYT1 TorsinA mutation. Conclusions: Our study demonstrates that PDE10A may act as translational biomarker in the external globus pallidus of animals with dystonia, which could be investigated in vivo by novel PDE10A PET ligands.